DESCRIPTION: (Applicant's abstract) The goal of this project is to examine the interactive role of gravity, innervation, and thyroid hormone (T3) in the developmental programming of myosin heavy chain (MHC) isoform expression in neonatal rodent antigravity and locomotor skeletal muscle. The central hypothesis to be tested is that gravity exerts a profound influence on the development and maintenance of slow (type I) MHC expression in antigravity and locomotor muscle, such that in its absence, a significant number of muscle cells up-regulate the expression of fast MHCs due to an increased responsiveness to thyroid hormone. In contrast, the normal expression of the fast IIx and IIb MHCs are developmentally regulated independently of gravity, but require both the presence of an intact nerve and T3 in order for these isoforms to reach full maturation in expression by replacing neonatal MHC isoforms. An additional objective is to determine whether muscle development, in the absence of gravity, creates a deleterious response whereby recovery from exposure to microgravity in the neonatal state, results in an irreversible effect on muscle mass and the pattern of adult myosin isoform expression. To test these hypotheses, both ground control and microgravity exposed neonatal rats (beginning at 2-3 days of age) will be allocated into the following subgroups: normal-control; denervated (DEN); thyroid deficient (TD); and DEN plus TD. The microgravity-exposed neonatal animals (along with the nursing Dams) will be subjected to spaceflight aboard the shuttle (Neurolab mission) for 18-21 days. At recovery (and 3-4 weeks following recovery), flight animals and ground controls will be processed so that key muscles will be obtained to study MHC isoform expression at both the mRNA and protein level of analysis using electrophoretic, immunohistochemical, and in situ hybridization technology. Collectively, these experiments will more clearly delineate the separate and interactive role of those key factors that have been shown to exert a strong influence on muscle development and contractile protein expression.